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Abstract

Introduction: Sunitinib malate (SM), an anti-cancer receptor tyrosine kinase inhibitor, causes cardiac dysfunction in a significant number of cancer patients (up to 20%) through a poorly understood mechanism. Using cardiac specific PDGFRβ KO mice we previously reported that PDGFRβ, the main target of SM, plays a crucial role in coronary microvascular and cardiac dysfunction.

We hypothesized that treatment with SM and CP673451 (CP), another small molecule PDGFR inhibitor, would phenocopy PDGFRβ KO mice with respect to coronary microvascular and cardiac dysfunction. We also tested if co-administration of thalidomide (TM), a reported vascular maturing agent (by inducing microvascular pericyte (PC) proliferation), was cardio-protective in SM induced cardiotoxicity.

Methods: Mice were divided into 6 groups for the following treatments: Vehicle Control (Ctl), SM (40mg/kg/day), SM+TM, (75mg/kg/alternate days), CP (40mg/kg/day), Ctl-transverse aortic constriction (Ctl-TAC), and SM-TAC for 14-21 days. MRI and Ultrasound were used to measure left ventricular ejection fraction (LVEF) and coronary flow reserve (CFR), respectively. NG2 and CD31 were used as markers for immunohistochemical assessment of coronary PC and endothelial cells, respectively.

Conclusion: Our findings suggest that the loss of coronary pericytes may be the primary cause of SM induced cardiotoxicity. Our data also suggests that treatment with TM (or other vascular maturing agents) may be a clinical approach for preventing cardiotoxicity due to SM and other anti-cancer agents targeting PDGFR.